The chemical name of dronedarone is N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy) benzoyl)-5-benzofuranyl)methanesulfonamide, the molecular formula is C31H44N2O5S and the molecular weight is 556.765 Dalton.
Dronedarone is a new antiarrhythmic drug developed by Sanofi-Aventis and is approved on Jul. 1, 2009 by the U.S. FDA.
The solubility of dronedarone in an aqueous solution is pH-dependent. The solubility of dronedarone at pH 3 to 5 is maximal (about 1 to 2 mg/ml), but its solubility at pH 6 to 7 is remarkably decreased (about 10 μg/ml at pH=7). The physiological pH from the stomach to the gut of a human body gradually increases, thus even if the drug is dissolved in the stomach after administration, the drug may still precipitate out after it enters the intestine through gastric emptying due to the increased pH. The drug cannot be kept in the intestinal juice in a molecular form and cannot achieve a transmembrane absorption due to the large amount of precipitation of it. This affects the absorption of the drug and leads to a low bioavailability. Thus, it is important to increase the dissolution rate of the drug so as to improve the bioavailability and clinical therapeutic effect. The solubility of the drug shall be increased with pharmaceutical technology to avoid its precipitation in a neutral medium, thereby improving the bioavailability of the drug.
In order to improve the solubility and the bioavailability of the said drug, a dronedarone hydrochloride injection is disclosed in an US patent application (US20040044070A1), according to which a β-cyclodextrin derivative is added into a buffer system (pH=3-5) to improve the solubility of the active ingredients. However, the method disclosed in that application has several disadvantages such as complex manufacturing process, low drug loading and poor stability. A solid pharmaceutical composition comprising benzofuran derivative is disclosed in a Chinese patent (ZL98808158.X), according to which the dronedarone hydrochloride will not precipitate out in a large amount after it is diluted in a high pH solution and then kept in a solution at pH 6-7 via the use of a non-ionotropic surfactant, especially poloxamer class of non-ionotropic surfactants. This improves the bioavailability of the drug under fasting conditions. However, surfactants used in that method will inevitably bring about a certain stimulatory effect and toxicity on human bodies. A capsule or tablet comprising a micronized dronedarone, surfactants and a hydrophilic polymer serving as a hydrotropy agent is disclosed in a Chinese patent application (CN 200610113479.5), according to which the cumulative dissolution rate of the capsule or tablet is greatly increased in a PBS at pH6.7. However, the method disclosed in this Chinese patent application also has several disadvantages such as a complex preparation process, high energy consumption, low drug loading, and dosage forms which are not suitable for the clinical application. Furthermore, anionic surfactants are used in that method, which have a certain stimulatory effect and toxicity on human bodies.
Currently, micronized technology, inclusion technique and solid dispersion technology are main methods to improve the solubility and dissolution rate of poorly soluble drugs. Existing studies show that, after being micronized, the particle sizes of a drug are reduced, the surface area and dissolution rate are increased. However when the particle sizes are reduced to a certain extent, the free energy of the microparticles is increased dramatically. The particles will spontaneously aggregate during storage, or after entering the body, resulting in reduced dissolution rate. Due to the restriction caused by the molecular weight and space structure of the drugs, the inclusion technology only has a low success rate. Even though an inclusion complex can be formed, there are still many problems such as low drug loading and the like.
A solid dispersion (SD) is a dispersion system present in a solid form formed by highly dispersing a drug into a solid carrier. The drug is present in the carrier in a form of molecular state, colloidal state, metastable state, microcrystalline state, and amorphous state, etc. The solubility and dissolution rate of the drug present in an amorphous state (high energy state) are larger than those of the drug present in other crystalline states.
There are relatively more researches in solid dispersion technique for improving the solubility and dissolution rate of poorly soluble drugs and more significant effects have been obtained. However there are also problems along with this technique, such as a complex process, a low drug loading and the like. Especially a large amount of carrier is required in order to achieve significant effects, which results in low drug loading and limited clinical use. For example, a pharmaceutical composition comprising a solid dispersion with the polymer matrix is disclosed in a Chinese patent application (CN101039657A), of which a solid dispersion is prepared with a hot melting extrusion method by using polydextrose and another polymer as a carrier. In order to achieve a desirable result, the method in that invention needs two carriers including polydextrose for the preparation of the solid dispersion, and the drug loading of which is low.
Therefore, there is a need to provide a solid dispersion of dronedarone or salts thereof, of which not only the solubility or dissolution rate is improved, but also a higher drug loading is achieved.